Radiotherapy is the most crucial nonsurgical therapeutic method in the multidisciplinary care of non-small cell lung cancer (NSCLC) patients. However, radiation resistance continues to be a significant clinical issue, negatively affecting cancer prognosis in patients. The analysis of the RNA microarray dataset revealed the dysregulation of the cell cycle, evasion of apoptosis and cancer immune response. A co-expression analysis with a network pharmacology approach revealed a lncRNA (ENST00000605056) regulating three highly ranked hub genes, driving radioresistance in NSCLC cells. The small molecules that target these RNAs offer therapeutic modulation of multiple biological processes. The study comprises three volatile ligands due to their good pharmacokinetic profile to target ENST00000605056. The molecular interaction studies uncovered their high binding affinity to its binding pocket with a preponderance of non-covalent bond interactions between the ligand atoms and the nucleotides. The Molecular dynamics simulations revealed the binding stability of ligands to the long non-coding RNA (lncRNA) with a very low deviation compared to the control. This study demonstrated the ability of the small molecules to target lncRNA in overcoming the global concern of radioresistance among NSCLC patients and aid in future translational studies.